Protein kinase Czeta represses the interleukin-6 promoter and impairs tumorigenesis in vivo.
Gene alterations in tumor cells that confer the ability to grow under nutrient- and mitogen-deficient conditions constitute a competitive advantage that leads to more-aggressive forms of cancer. The atypical protein kinase C (PKC) isoform, PKCzeta, has been shown to interact with the signaling adapter p62, which is important for Ras-induced lung carcinogenesis. Here we show that PKCzeta-deficient mice display increased Ras-induced lung carcinogenesis, suggesting a new role for this kinase as a tumor suppressor in vivo. We also show that Ras-transformed PKCzeta-deficient lungs and embryo fibroblasts produced more interleukin-6 (IL-6), which we demonstrate here plays an essential role in the ability of Ras-transformed cells to grow under nutrient-deprived conditions in vitro and in a mouse xenograft system in vivo. We also show that PKCzeta represses histone acetylation at the C/EBPbeta element in the IL-6 promoter. Therefore, PKCzeta, by controlling the production of IL-6, is a critical signaling molecule in tumorigenesis.
Galvez
Anita S
AS
Department of Cancer and Cell Biology, University of Cincinnati College of Medicine, 3125 Eden Ave., Cincinnati, OH 45267, USA.
Duran
Angeles
A
Linares
Juan F
JF
Pathrose
Peterson
P
Castilla
Elias A
EA
Abu-Baker
Shadi
S
Leitges
Michael
M
Diaz-Meco
Maria T
MT
Moscat
Jorge
J
D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics*; D008175:Lung Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011493:Protein Kinase C / Q000172:deficiency / Q000378:metabolism*; D044967:Serum; D014158:Transcription, Genetic; D000099221:Protein Kinase C zeta
D015850:Interleukin-6; D016328:NF-kappa B; D011493:Protein Kinase C; D000099221:Protein Kinase C zeta